title: Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity.
abstract: Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations.
authors.affiliation: Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY 13210.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Rochford
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Paul C
authors.initials: PC
authors.lastname: Baresel
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Magill
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
mesh_terms: D000634:Aminoquinolines / Q000009:adverse effects / Q000627:therapeutic use; D000743:Anemia, Hemolytic / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis*; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use; D002738:Chloroquine / Q000009:adverse effects / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003622:Dapsone / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000009:adverse effects / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004906:Erythrocyte Count; D017707:Erythrocyte Transfusion / Q000379:methods*; D005260:Female; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000097:blood / Q000628:therapy*; D006801:Humans; D015767:Mefloquine / Q000009:adverse effects / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011319:Primaquine / Q000009:adverse effects / Q000627:therapeutic use*; D011739:Pyrimethamine / Q000009:adverse effects / Q000627:therapeutic use; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine; D002738:Chloroquine; D003622:Dapsone; C004331:pamaquine; D011319:Primaquine; D004318:Doxycycline; D015767:Mefloquine; C080436:8-aminoquinoline; D011739:Pyrimethamine